Project Summary/Abstract Obesity is a pressing medical need: it affects one-third of adults in the US, and more than 80% of people with diabetes mellitus are overweight or obese. In animal models, multiple obesity-related pathways lead to pulmonary hypertension (PH), including insulin resistance, inflammation, oxidative stress, and adipokine signaling. Few studies have examined the association of metabolic dysfunction and PH in humans. We postulate that obesity-related metabolic disease leads to pulmonary vascular dysfunction, and may represent an early phenotype in the transition to heart failure. It is recognized that metabolic disease leads to endothelial dysfunction; when localized to the pulmonary circulation, pulmonary endothelial dysfunction is an integral driver of the pathobiology of PH. We hypothesize that metabolic disease may lead to pulmonary artery endothelial cell (PAEC) dysfunction as a driver of PH. We propose to study 250 obese non-diabetic individuals with exertional dyspnea. To gain further insights into underlying mechanisms of obesity-related PH, we will pursue three related lines of investigation: In Aim 1, we will investigate the association of metabolic disease and pulmonary artery endothelial cell (PAEC) phenotype with pulmonary hemodynamics in human subjects. Using a novel technique to isolate fresh human PAECs at the time of right heart catheterization, we will profile PAEC phenotypes including endothelial insulin signaling (insulin-mediated endothelial nitric oxide synthase phosphorylation) and adenosine monophosphate-activated protein kinase activation. In Aim 2, we will study the dynamic pulmonary vascular responses to cardiopulmonary exercise testing in metabolic disease. Pulmonary vascular function will be precisely characterized at rest and during cycle ergometry exercise testing with simultaneous hemodynamic monitoring in order to evaluate multi-point pulmonary artery pressure-cardiac output relationships and pre- and post-capillary components of PH. In Aim 3, we will conduct a randomized intervention study, to examine the effect of metformin versus placebo on pulmonary vascular function and PAEC phenotype in obese individuals. This proposal leverages a unique multidisciplinary team of collaborators with expertise in cardiovascular and metabolic disease, endothelial biology, PH, exercise physiology, endocrinology, and biostatistics. These studies have the potential to provide important insights into mechanisms driving PH in metabolic disease, and will lay the foundation for future studies focused on disease prevention and optimal therapies in obesity-related cardiovascular disease.